Diclofenac sodium oral pharmaceutical

ABSTRACT

The present invention relates to a diclofenac sodium oral pharmaceutical containing diclofenac sodium, a nonionic surfactant, a cholic acid derivative as an absorption promoting agent, and a glycerin or a glycol. 
     The oral pharmaceutical has a rapid-acting effect and a good internal absorption even under non-fasting condition. Further, the pharmaceutical can be processed in a hard capsule pharmaceutical by filling it in a hard capsule as such, and has an excellent internal absorption under non-fasting condition, similarly to suppositories.

TECHNICAL FIELD

The present invention relates to a rapid-acting diclofenac sodium oralpharmaceutical.

BACKGROUND ART

Diclofenac sodium (Monosodium 2-(2,6-dichloroanilino) phenyl acetate,C₁₄H₁₀C₁₂NNaO₂) is a nonsteroidal drug having analgesic,anti-inflammatory and anti-rheumatic effects which was developed byCIBA-GEIGY AG in Switzerland (now, Novartis Pharma AG) in 1965. Thisdrug has a strong action and a low toxicity compared with indomethacinor the like, and therefore is widely subjected to current clinical use.

The commercially available diclofenac sodium pharmaceuticals includetablets, delayed-release pharmaceuticals and suppositories, etc. Amongthem, oral pharmaceuticals are formulated for rapid-acting effect.However, it is recommended to avoid taking them on an empty stomach asthey have side effects such as stomach discomfort.

However, the absorption of diclofenac sodium oral pharmaceuticals isoutstandingly effected on whether or not a meal has been eaten. Whenthey are taken after eating, the initial absorption of diclofenac sodiumis outstandingly reduced in the amount and delayed in the rate comparedwith the case where they are taken on an empty stomach, and in somecases, the maximum absorption is confirmed at several hours to ten andseveral hours after taking them, and also individual difference is largein the absorption thereof.

Therefore, in case where an rapid-acting effect and certainty are takenseriously, it is the present state that the pharmaceuticals are used inmost cases in a form of suppository. However, there are many patientswho are reluctant to use the suppositories, and therefore thesuppositories can not be used as conveniently as oral pharmaceuticals.Consequently, today there is a strong request for diclofenac sodium oralpharmaceuticals having a rapid-acting effect and certainty similarly tothe suppository even in case where it is taken on a non-empty stomach.

It has been already known that in order to increase an internalabsorption of a pharmaceutical agent that is slightly soluble in water,the pharmaceutical agent is formulated with a surfactant to increase thesolubility of the pharmaceutical agent to water.

As the prior document, Japanese Patent Laid-open No. Sho 63-277617discloses a medicine composition for oral administration from whichmicelles are formed, comprising an nonsteroidal anti-inflammatory agentsuch as diclofenac, and a nonionic surfactant such as polyoxyethylatedsurfactant, sorbitan fatty acids or the like. In addition, the examplesof this document describe a pharmaceutical comprising diclofenac acidand polyoxyethylated castor oil. However, this document does notdescribe at all the above-mentioned problem on the absorption ofdiclofenac sodium pharmaceutical under non-fasting condition nor meansfor solving the problem. Further, this document does not describe assurfactant cholic acid derivatives that are varieties of anionicsurfactants.

In addition, Japanese Patent Laid-open No. Hei 8-507515 discloses aparticle-suspension of colloidal solid particles in which apharmaceutical agent being slightly soluble in water is captured withsolid particles that are emulsified and stabilized by adding a lipidthat is insoluble or slightly soluble in water at room temperature tononionic surfactant and bile salts containing propylene glycol asdispersant, and this document discloses that the pharmaceutical agentincludes diclofenac. However, this document has no concrete disclosureon diclofenac pharmaceuticals. Also, this document does not describeproblems to be solved by the present invention nor means for solving theproblems similarly to the above-mentioned Japanese Patent Laid-open No.Sho 63-277617.

As mentioned above, although it was known that diclofenac being slightlysoluble in water is mixed with surfactants in order to increasesolubility and dispersibility, it was not necessary to use surfactantsfor diclofenac sodium having a higher water-solubility, and thereforethe mixing of surfactants has not been considered.

DISCLOSURE OF THE INVENTION

Under the above-mentioned circumstances, the present inventor earnestlyinvestigated and repeatedly considered to make diclofenac sodium oralpharmaceuticals rapid-acting under non-fasting condition by producingpharmaceuticals comprising a variety of substances such as surfactants,absorption promoting agent, melting point modifiers, solubilizing agentsand viscosity modifiers, etc. and by using them in a test of kinetics inrat blood under non-fasting condition and in a dissolution test. As theresults, the inventor found that diclofenac sodium oral pharmaceuticalshave an excellent absorption under non-fasting condition by mixing anonionic surfactant, a cholic acid derivative represented by deoxycholicacid as absorption promoting agent, and a glycerin or a glycol asmelting point modifier (used for lowering melting point) with diclofenacsodium. Consequently, the present invention was completed on the basisof the finding.

That is, the present invention provides a diclofenac sodium oralpharmaceutical characterized by containing diclofenac sodium, a nonionicsurfactant, a cholic acid derivative as an absorption promoting agent,and a glycerin or a glycol.

In addition, the present invention provides a diclofenac sodium oralpharmaceutical, which is filled in a hard capsule.

The rapid-acting diclofenac sodium oral pharmaceutical of the presentinvention is in a liquid state in which mixed compositions are dissolvedeach other or in a solid state in which the mixed compositions in aliquid state are solidified, and is not in a state of aparticle-suspension in which a pharmaceutical agent is captured withcarrier solid particles that is disclosed in Japanese Patent Laid-openNo. Hei 8-507515.

And, the pharmaceutical of the present invention can be processed in anoral pharmaceutical by filling it in a hard capsule as such. Thematerial of this hard capsule is preferably hydroxypropylmethylcellulose(HPMC). The rapid-acting diclofenac sodium oral pharmaceutical of thepresent invention can be also filled in a soft capsule, processed in anoral liquid by dissolving it in water or the like, pulverized by mixingit with a pulverization agent, granulated or processed in tablets.Further, these pharmaceuticals can be combined with a delayed-releasepharmaceutical.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing initial kinetics in blood of rat (n=6,non-fasting condition) to which the pharmaceuticals produced in Example1 and 2 according to the present invention, and a tablet (ComparativeExample 1) and a suppository (Comparative Example 2) of commerciallyavailable diclofenac sodium was administered;

FIG. 2 is a graph showing initial kinetics in blood of rat (n=6,non-fasting condition) to which the pharmaceuticals produced in Example3 according to the present invention;

FIG. 3 is a graph showing the results of the dissolution test on thepharmaceuticals indicated in Examples 1 and 2 according to the presentinvention and a commercially available diclofenac sodium tablet; and

FIG. 4 is a graph showing the results of the dissolution test (n=6) onthe pharmaceutical indicated in Example 3 according to the presentinvention and a commercially available diclofenac sodium tablet.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, each component of the oral pharmaceutical to be mixed alongwith the active ingredient in the present invention, diclofenac sodiumwill be described in further detail.

The nonionic surfactant used for the diclofenac sodium oralpharmaceutical of the present invention is a surfactant having littletoxicity in oral administration, and can be used in a combination of twoor more. Examples of the nonionic surfactant include saturatedpolyglycolated glycerides, polyoxyethylene sorbitan fatty acid esters(polysorbates) and polyglycerin fatty acid esters, polyoxyethyleneglycerin fatty acid ester deoxycholic acids, sucrose fatty acid esters,lecithin derivatives, propyleneglycol fatty acid esters, glycerin fattyacid esters, sorbitan fatty acid esters, polyoxyethylene sorbit fattyacid esters, polyoxyethylene lanolin/lanolin alcohol/bees waxderivatives, polyoxyethylene castor oil/hardened castor oil,polyoxyethylene sterol/hydrogenated sterol polyethyleneglycol fatty acidesters, polyoxyethylene alkyl ethers, polyoxyethylene polyoxypropylenealkyl ethers, polyoxyethylene phenyl ethers, polyoxyethylene alkylphenyl formaldehyde condensation products, and polyoxyethylenepolyoxypropylene glycol, and the like. Among them, nonionic surfactantshaving a relatively high HLB value (HLB=10 to 20) are preferable.

The cholic acids derivatives as the absorption promoting agent used forthe diclofenac sodium oral pharmaceutical of the present inventionincludes for example lithocholic acid, deoxycholic acid,glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid,glycochenodeoxycholic acid, taurochenodeoxycholic acid, ursodeoxycholicacid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, cholic acid,glycocholic acid, taurocholic acid, ursocholic acid, glycoursocholicacid, tauroursocholic acid and the salts thereof such as sodium salt orpotassium salt, etc. These cholic acid derivatives may be used in acombination of two or more.

The melting point modifiers used for the diclofenac sodium oralpharmaceutical of the present invention includes for example glycerin,polyethyleneglycols, propyleneglycols or a combination of two or moreselected from these compounds. These melting point modifiers are usedalso as solubilizing agents.

The formulating ratio of the pharmaceuticals is as follows. The nonionicsurfactant can be added in an amount of 0.05 to 20 parts by weight,preferably 1 to 5 parts by weight based on 1 part by weight ofdiclofenac sodium. In addition, the absorption promoting agent andmelting point modifier may be added in an appropriate amount accordingto need, preferably based on 1 part by weight of diclofenac sodium, theabsorption promoting agent is added in an amount of 0.01 to 5 parts byweight, preferably 0.05 to 0.5 part by weight, and the melting pointmodifier is added in an amount of 0.1 to 10 parts by weight, preferably1.0 to 5.0 parts by weight.

A preferable formulation example for the pharmaceutical of the presentinvention comprises diclofenac sodium, and saturated polyglycolatedglyceride (for example Gelucire 44/14 (trade name) manufactured byGattefosse in France) or polyoxyethylene sorbitan fatty acid ester (forexample, NIKKOL TS-10 (trade name), Polysorbate 60, manufactured byNikko Chemicals Co., Ltd.) as nonionic surfactant, deoxycholic acid asabsorption promoting agent and propylene glycol as melting pointmodifier. More preferable formulation example for the pharmaceuticalcomprises diclofenac sodium, and deoxycholic acid, hexaglycerylmonolaurate (for example NIKKOL Hexaglyn 1-L (trade name), manufacturedby Nikko Chemicals Co., Ltd.) and propylene glycol, preferably in aweight ratio of 1:0.1:3.5:1.8.

The diclofenac sodium oral pharmaceuticals were prepared by using thesurfactants, absorption promoting agents and melting point modifiers asmentioned above. The pharmaceuticals showed the most excellent initialkinetics in rat blood (non-fasting) and a high dissolution rate in thefirst fluid of Disintegration Test specified in The JapanesePharmacopoeia.

Further, the diclofenac sodium oral pharmaceuticals of the presentinvention may contain other solubilizing agents, viscosity modifiers andexcipients which are commonly used for pharmaceuticals, if necessary.

EXAMPLES

Next, the present invention will be concretely described by showingexamples to which the present invention is not be limited.

Example 1

In a glass bottle with screw-cap, 100 g of pulverized diclofenac sodiumwas weighed, then 350 g of saturated polyglycolated glyceride (Gelucire44/14 (trade name) manufactured by Gattefosse in France), 10 g ofdeoxycholic acid and 120 g of propyleneglycol were added therein. Amagnet bar was placed in the glass bottle which then was sealed with ascrew cap. The resulting mixture sealed in the glass bottle was stirredin a water bath at 70° C. After diclofenac sodium and deoxycholic acidwere dissolved, the resulting formulations were filled in a hard capsule(about 2 mm x about 8 mm) in an amount containing 5 mg of diclofenacsodium in hot state with an injector to obtain a rapid-acting diclofenacsodium pharmaceutical. The resulting hard capsule pharmaceutical wasallowed to stand at room temperature for at least one day in order to bestabilized.

Example 2

350 of polyoxyethylene sorbitan fatty acid ester (NIKKOL TS-10 (tradename), Polysorbate 60, manufactured by Nikko Chemicals Co., Ltd.) wasused in the place of saturated polyglycolated glyceride used in Example1, and a pharmaceutical was obtained according to the procedures ofExample 1.

Example 3

(parts by weight) Pulverized diclofenac sodium 1 Deoxycholic acid 0.1NIKKOL Hexaglyn 1-L 3.5 (hexaglyceryl monolaurate, HLB = 14.5,manufactured by Nikko Chemicals Co., Ltd.) Propylene glycol 1.8

According to the above-mentioned formulation, an appropriate amount ofHexaglyn 1-L was weighed in a glass bottle with screw-cap, and thenother remaining components mentioned above were added therein. A magnetbar was placed in the glass bottle which then was sealed with a screwcap. The resulting mixture sealed in the glass bottle was stirred in awater bath while heating at nearly 70° C. After solid contents werecompletely dissolved, the resulting formulations were filled in a hardcapsule in an amount containing 5 mg of diclofenac sodium in hot statewith an injector.

The resulting capsule pharmaceutical was allowed to stand at roomtemperature for at least one day in order to be stabilized. Even afterstanding, diclofenac sodium and deoxycholic acid were notrecrystallized, and the obtained pharmaceutical remained stable.

Comparative Example 1

Commercially available diclofenac sodium pharmaceutical (trade mark:Voltaren Tablet, one tablet (about 150 mg) contains 25 mg of diclofenacsodium, manufactured by Novartis Pharma AG) was scraped down with acutter in such a manner that the scraped pharmaceutical (about 30 mg)contains diclofenac sodium in the same amount (5 mg) as that in theabove-mentioned test pharmaceutical. The resulting scrapedpharmaceutical was used as oral pharmaceutical.

Comparative Example 2

Commercially available diclofenac sodium pharmaceutical (trade mark:Voltaren Suppo, one suppository (about 1 g) contains 25 mg of diclofenacsodium, manufactured by Novartis Pharma AG) was scraped down with acutter in such a manner that the scraped pharmaceutical (about 0.2 g)contains diclofenac sodium in the same amount (5 mg) as that in theabove-mentioned test pharmaceutical, and that the pharmaceutical has asharpen tip in order to be easily inserted in the anus. The resultingscraped pharmaceutical was used as suppository.

Test Example 1 Test of Kinetics in Rat Blood on Concentration

Each of the above-mentioned pharmaceuticals was orally or rectallyadministered to rats under non-fasting condition.

After rats (wister strain, male, body weight on arrival: 230 g) werepreliminarily fed for one week, a rat was placed in a cage, and for 24hours from the day before the test to the day thereof the rats wereplaced under fasting condition where only water was fed, and thereafterabout 0.5 g of a solid feed was fed. 30 minutes later, six rats whichate completely the feed were used per each test condition. Afterslightly anesthetizing the rats with ether, the pharmaceuticals ofExamples 1 to 3 and Comparative Example 1 were orally administered byusing a catheter reaching the stomach. The suppository of ComparativeExample 2 was rectally administered by inserting it from the anus. Then4 ml of water was orally administered and then every ca. 15 minutes, ca.30 minutes and ca. 120 minutes, blood was collected from each rat,diclofenac in the serum was measured (measurement method: HPLC method),and the concentration in the serum was calculated from the measuredvalue.

FIG. 1 is a graph showing initial kinetics in blood, the data in whichwere plotted with concentration of diclofenac in serum of rat(non-fasting) after administration of the pharmaceutical of Example 1 or2, or Comparative Example 1 or 2 as ordinate and time as abscissa.

As shown in this graph, it is understood that the pharmaceuticalsproduced in Examples 1 and 2 according to the present invention areexcellent in initial kinetics in blood compared with commerciallyavailable diclofenac sodium tablet (Comparative Example 1) and that thepharmaceuticals of the present invention have kinetics in blood near tothat of commercially diclofenac sodium suppository (Comparative Example2) rather than that of commercially available diclofenac sodium tablet.

In addition, FIG. 2 is a graph showing initial kinetics in blood, thedata in which were plotted with concentration of diclofenac in serum ofrat (non-fasting) after administration of the pharmaceutical of Example3 as ordinate and time as abscissa.

It is understood that the pharmaceutical produced in Example 3 indicatesalso an excellent initial kinetics in blood similarly to those producedin Examples 1 and 2 according to the present invention.

Test Example 2 Dissolution Test

Rapid-acting diclofenac sodium pharmaceuticals were prepared by fillingin a hard capsule, pharmaceutical formulations prepared in Example 1 or2 containing diclofenac sodium in an amount of 25 mg. Thesepharmaceuticals filled in a hard capsule and commercially availablediclofenac sodium tablet (containing diclofenac sodium in an amount of25 mg) were subjected to a dissolution test by the method (paddlemethod, 50 rotations/minute, dissolution fluid (the first fluid ofaccording to Disintegration Test specified in The Japanese Pharmacopoeia(artificial gastric juice), pH 1.2, 900 mL, 37° C.)) according toDisintegration Test specified in The Japanese Pharmacopoeia. About 2.5,5, 10, 15, 20 and 30 minutes after starting the test, the dissolutionfluid was taken out, the concentration of diclofenac sodium dissolvedfrom the pharmaceutical was measured and the dissolution rate wascalculated therefrom

The results are shown in the graph of FIG. 3. It is understood that thepharmaceuticals produced in Examples 1 and 2 according to the presentinvention have a higher dissolution rate than commercially availablediclofenac sodium tablet.

In addition, the pharmaceutical formulations prepared in Example 3 werefilled in a hard capsule so as to contain diclofenac sodium in an amountof 25 mg and allowed to stand at room temperature for one day or more inorder to be stabilized. This pharmaceutical filled in a hard capsule wassubjected to a dissolution test by the method (paddle method, 100rotations/minute, dissolution fluid (the first fluid of according toDisintegration Test specified in The Japanese Pharmacopoeia (artificialgastric juice), pH 1.2, 900 mL, 37° C.)) according to DisintegrationTest specified in The Japanese Pharmacopoeia. The results are shown inthe graph of FIG. 4. It is understood from this graph that thepharmaceutical produced in Example 3 has dissolution characteristicssimilar to the pharmaceuticals produced in Examples 1 and 2.

It is clear from these results of the examples in which diclofenacsodium shows an excellent initial kinetics in blood of rat in anon-fasting state and a high dissolution rate in the dissolution teststhat the diclofenac sodium oral pharmaceuticals of the present inventionhave unique physical properties compared with commercially availableoral pharmaceuticals and are excellent in internal absorption even innon-fasting state.

INDUSTRIAL APPLICABILITY

As described above, the diclofenac sodium oral pharmaceutical of thepresent invention which is formulated according to the present inventionand used under non-fasting condition has a rapid-acting effectcomparable to the suppository thereof. Therefore, the pharmaceutical canbe effectively used for cure as oral pharmaceutical which patients canaccept easily on administration thereof.

1. An oral pharmaceutical comprising a diclofenac sodium, a nonionic surfactant, a cholic acid derivative as an absorption promoting agent, and a glycerin or a glycol, wherein the cholic acid derivative is selected from the group consisting of lithocholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, ursodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, cholic acid, glycocholic acid, taurocholic acid, ursocholic acid, glycoursocholic acid, tauroursocholic acid and the salts thereof, wherein the pharmaceutical is in a liquid state in which the diclofenac sodium, the nonionic surfactant, the cholic acid derivative, and the glycerin or the glycol are dissolved.
 2. The oral pharmaceutical according to claim 1, wherein the pharmaceutical contains 0.05 to 20 parts by weight of the nonionic surfactant based on 1 part by weight of the diclofenac sodium, 0.01 to 5 parts by weight of the cholic acid derivative as the absorption promoting agent based on 1 part by weight of the diclofenac sodium, and 0.1 to 10 parts by weight of the glycerin or glycol based on 1 part by weight of the diclofenac sodium.
 3. The oral pharmaceutical according to claim 1, which is filled in a hard capsule.
 4. The oral pharmaceutical according to claim 2, which is filled in a hard capsule.
 5. The oral pharmaceutical according to claim 1, further comprising a delayed-release pharmaceutical.
 6. The oral pharmaceutical according to claim 2, further comprising a delayed-release pharmaceutical.
 7. The oral pharmaceutical according to claim 3, further comprising a delayed-release pharmaceutical.
 8. The oral pharmaceutical according to claim 4, further comprising a delayed-release pharmaceutical. 